Metabolic Dysfunction in Alzheimer’s Disease: Brain Glucose Hypometabolism as an Early Precursor to Amyloid and Tau Pathology

TL;DR

This paper reviews how brain glucose metabolism problems may come before and contribute to Alzheimer’s disease pathology like amyloid and tau buildup.

Contribution

The paper highlights metabolic dysfunction as an early and critical driver of Alzheimer’s disease, preceding amyloid and tau pathology.

Findings

Cerebral glucose hypometabolism and mitochondrial issues are present early in Alzheimer’s disease.

Metabolic changes are more closely linked to tau pathology and cognitive decline than to amyloid accumulation.

Early microglial activation is associated with glucose hypermetabolism that later shifts to hypometabolism and neurodegeneration.

Abstract

Objective: Alzheimer’s disease (AD) is traditionally characterized by amyloid-β and tau pathology; however, accumulating evidence indicates that metabolic and inflammatory dysfunctions are early, central contributors to disease development. This narrative review explores how metabolic disturbances influence AD pathophysiology. Methods: A comprehensive literature search was performed on PubMed, Embase, and Scopus. Selected studies were original studies or reviews published in English within the past five years involving human subjects. Case reports, case series, editorials, and non-human studies were excluded. A total of 64 articles were reviewed and summarized. Results: Cerebral glucose hypometabolism, mitochondrial impairment, insulin resistance, oxidative stress, and neuroinflammation were observed throughout the AD spectrum. These metabolic changes often appeared before significant amyloid accumulation and were more closely linked to tau pathology and cognitive decline. Early microglial activation was linked to transient glucose hypermetabolism, progressing to glucose hypometabolism and neurodegeneration as the disease advanced. Conclusions: AD is associated with a gradual breakdown of metabolic and inflammatory homeostasis, which occurs before and promotes the development of traditional neuropathological features. Addressing early metabolic vulnerabilities may be essential for effective disease intervention and prevention.

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